A type of drug for which a correlation between biological activity and structure has been found is the metal chelating agent such as iron, ruthenium, cobalt, manganese, zinc and copper (Dwyer, F. F. et al. Nature. 179, (1956), 425-426). Chelating agents can be designed to inactive bacteria, viruses and fungi by capturing the metallic ions necessary for the metabolism of these microorganisms. They can also be supplied with metallic ions that prove toxic to them.
Studies related to the composition of physiological fluids have shown that the metallic ions present in these systems are largely found in the form of mixed complexes. Here the term mixed complex must be understood to mean all those coordination complexes with two or three chelate type ligands that are different one from the other, excluding the solvent of the chelate ligand category.
Sigel and colleagues (Sigel, H. et al., JACS 99:13 (1976), 4489-4496) have shown that in many cases the enzymatic action depends on an elementary process in which an enzyme-substrate complex is generated that presents characteristics analogous to those of a mixed complex.
Certain metallic chelates supplied in small concentrations are active agents against some bacteria, fungi, viruses and some tumorous cells.
It is well known, for instance, that Staphylococcus pyrogenes, which has been detected in infected wounds and has proved to be highly resistant to the action of many standard antibiotics, perishes in the presence of the iron (tetramethyl 1, 1, 10-phenanthroline).sub.3 (acetylacetonate)+ and ruthenium (tetramethyl-1, 10 phenanthroline).sub.2 (acetylacetonate)+ complexes. The biological activity of these saturated chelate complexes is principally due to the stereochemistry of the complex as a whole, the ionic nature of the coordinating sphere, the nature of the coordination center, the lyophilicity of the ligands, the redox potentials of the complexes, the thermodynamic stability and kinetic of the metallic chelates.
Volpir and colleagues have studied the catalytic activity of the Co (II) and Cu (II) complexes with orthophenanthrolines in the oxidation processes of the NADH, Q.sub.4 H.sub.2 (quinone), Q.sub.9 H.sub.2 (ubiquinone) and cytochrome C substrates.
The [Cu(2,9-dimethyl-1,1-phenanthroline)].+-.Cl.sub.2 complex is an effective inhibitor of the growth of the plasmodium Microplasmacillisepticum, a very dangerous pathogenic microorganism that induces pulmonary diseases in man.
D. R. Williams has calculated the distribution percentages of the Cu(II), Fe(II), Mn(II) and Zn(II) ions with low weight ligands, the predominant molecules in human blood plasma; Cu (hys) (Cys); (ulhys).sub.2 and Cu (hys) (CysH).sup.+ are among the most abundant complexes. Mention is made in the literature of studies on the absorption of the Mn (gly).sub.2 and Mn(L-ala).sub.2 chelate complexes through the intestinal wall in dogs.
Kwik and colleagues have reported the synthesis of mixed complexes with the general formula [Cu(phenanthroline) (aminoacidate)]nH.sub.2 O, [Cu (bipyridine) (aminoacidate)]n H.sub.2 O, [Cu (phenanthroline) (aminoacidate) (Cl, O.sub.2, SO.sub.4)]nH.sub.2 O where the aminoacidate is the glycinate, alaninate, valinate, tyrosinate, serinate, aspartate or glutamate ion.
Where the general synthesis method consists of preparing an aqueous solution with 5 mmol of CuSO.sub.4. 5H.sub.2 O in 20 ml of distilled water which is slowly added to an ethanolic solution with 8 mmoles of o-phenanthroline in 20 ml of ethanol, a solution blue in color is immediately formed. The mixture is magnetically shaken and at the same time a solution of 10 ml of HC1 0.1 M containing one of the aminoacidates is added slowly, immediately followed by a solution of ammonium hydroxide 1 M until the solution becomes clear. The mixture that has been thus prepared is heated and shaken for 30 minutes; the heating process is continued until the volume is reduced by half, the product obtained is cooled in ice until a solid is formed, it is filtered, washed in small pieces in cold water and is then in ethanol and is finally vacuum dried.
The applicant has developed a process to obtain new chelates by means of the synthesis and characterization of mixed chelate complexes of ions Mn (II), Fe (II), Ni (II), Co (II, III), Cu (II) Zn (II) and Ru (II) with ligands of the N-N (phenanthrolines and bipyridines), O-O (acethylacetonate and salicilaldehydate ions) and N-O (aminocidate ions) type. These mixed chelate complexes have some type of potential biological activity.
With the ion Cu (II) in particular 6 new mixed complexes of the [Cu (N-N) (N-O)].sup..+-. NO.sub.3 type have been isolated.